Zhou Li-Jun, Chen Xue-Ying, Liu Shui-Ping, Zhang Lin-Lin, Xu Ya-Nan, Mu Pan-Wei, Geng Deng-Feng, Tan Zhi
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
J Am Heart Assoc. 2017 Jul 27;6(8):e005754. doi: 10.1161/JAHA.117.005754.
Percutaneous coronary intervention has been widely used in the treatment of ischemic heart disease, but vascular restenosis is a main limitation of percutaneous coronary intervention. Our previous work reported that caveolin-1 had a key functional role in intimal hyperplasia, whereas whether Cavin-1 (another important caveolae-related protein) was involved is still unknown. Therefore, we will investigate the effect of Cavin-1 on neointimal formation.
Balloon injury markedly reduced Cavin-1 protein and enhanced ubiquitin protein expression accompanied with neointimal hyperplasia in injured carotid arteries, whereas Cavin-1 mRNA had no change. In cultured vascular smooth muscle cells (VSMCs), Cavin-1 was downregulated after inhibition of protein synthesis by cycloheximide, which was distinctly prevented by pretreatment with proteasome inhibitor MG132 but not by lysosomal inhibitor chloroquine, suggesting that proteasomal degradation resulted in Cavin-1 downregulation. Knockdown of Cavin-1 by local injection of Cavin-1 short hairpin RNA (shRNA) into balloon-injured carotid arteries in vivo promoted neointimal formation. In addition, inhibition or overexpression of Cavin-1 in cultured VSMCs in vitro prompted or suppressed VSMC proliferation and migration via increasing or decreasing extracellular signal-regulated kinase phosphorylation and matrix-degrading metalloproteinases-9 activity, respectively. However, under basic conditions, the effect of Cavin-1 on VSMC migration was stronger than on proliferation. Moreover, our results indicated that Cavin-1 regulated caveolin-1 expression via lysosomal degradation pathway.
Our study revealed the role and the mechanisms of Cavin-1 downregulation in neointimal formation by promoting VSMC proliferation, migration, and synchronously enhancing caveolin-1 lysosomal degradation. Cavin-1 may be a potential therapeutic target for the treatment of postinjury vascular remodeling.
经皮冠状动脉介入治疗已广泛应用于缺血性心脏病的治疗，但血管再狭窄是经皮冠状动脉介入治疗的主要局限性。我们之前的研究报道小窝蛋白-1在内膜增生中起关键作用，而小窝装配蛋白-1（另一种重要的小窝相关蛋白）是否参与其中仍不清楚。因此，我们将研究小窝装配蛋白-1对新生内膜形成的影响。
球囊损伤显著降低损伤颈动脉中小窝装配蛋白-1的表达并增强泛素蛋白表达，同时伴有新生内膜增生，而小窝装配蛋白-1的mRNA无变化。在培养的血管平滑肌细胞（VSMC）中，用放线菌酮抑制蛋白质合成后小窝装配蛋白-1表达下调，蛋白酶体抑制剂MG132预处理可明显阻止这种下调，但溶酶体抑制剂氯喹不能，这表明蛋白酶体降解导致小窝装配蛋白-1下调。通过向体内球囊损伤的颈动脉局部注射小窝装配蛋白-1短发夹RNA（shRNA）敲低小窝装配蛋白-1可促进新生内膜形成。此外，体外培养的VSMC中抑制或过表达小窝装配蛋白-1分别通过增加或降低细胞外信号调节激酶磷酸化和基质降解金属蛋白酶-９活性来促进或抑制VSMC增殖和迁移。然而，在基础条件下，小窝装配蛋白-1对VSMC迁移的影响强于对增殖的影响。此外，我们的结果表明小窝装配蛋白-1通过溶酶体降解途径调节小窝蛋白-1的表达。
我们的研究揭示了小窝装配蛋白-1下调通过促进VSMC增殖、迁移并同步增强小窝蛋白-1溶酶体降解在新生内膜形成中的作用及机制。小窝装配蛋白-1可能是治疗损伤后血管重塑的潜在治疗靶点。
